The online version of this article (doi:10.1186/1477-7827-10-15) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
LF participated in the study design, carried out experiments and prepared the manuscript. CGW performed histopathological and immunohistochemical analysis and contributed to the manuscript preparation. SS and NK collected the human placenta samples, extracted placental proteins and participated in Western blotting analysis. JIS and TH formulated the research questions, conceived the study and participated in drafting of the manuscript. DM participated in the development of critical methodology and the manuscript preparation. All authors read and approved the final manuscript.
Placental malfunction in preeclampsia is believed to be a consequence of aberrant differentiation of trophoblast lineages and changes in utero-placental oxygenation. The transcription factor Snail, a master regulator molecule of epithelial-mesenchymal transition in embryonic development and in cancer, is shown to be involved in trophoblast differentiation as well. Moreover, Snail can be controlled by oxidative stress and hypoxia. Therefore, we examined the expression of Snail and its downstream target, e-cadherin, in human normal term, preterm and preeclamptic placentas, and in pregnant rats that developed preeclampsia-like symptoms in the response to a 20-fold increase in sodium intake.
Western blotting analysis was used for comparative expression of Snail and e- cadherin in total protein extracts. Placental cells expressing Snail and e-cadherin were identified by immunohistochemical double-labeling technique.
The levels of Snail protein were decreased in human preeclamptic placentas by 30% (p < 0.01) compared to normal term, and in the rat model by 40% (p < 0.001) compared to control placentas. In preterm placentas, the levels of Snail expression varied, yet there was a strong trend toward statistical significance between preterm and preeclamptic placentas. In humans, e-cadherin protein level was 30% higher in preeclamptic (p < 0.05) placentas and similarly, but not significantly (p = 0.1), high in the preterm placentas compared to normal term. In the rat model of preeclampsia, e-cadherin was increased by 60% (p < 0.01). Immunohistochemical examination of human placentas demonstrated Snail-positive staining in the nuclei of the villous trophoblasts and mesenchymal cells and in the invasive trophoblasts of the decidua. In the rat placenta, the majority of Snail positive cells were spongiotrophoblasts of the junctional zone, while in the labyrinth, Snail-positive sinusoidal giant trophoblasts cells were found in some focal areas located close to the junctional zone.
We demonstrated that human preeclampsia and the salt-induced rat model of preeclampsia are associated with the reduced levels of Snail protein in placenta. Down-regulation of the transcription factor Snail in placental progenitor cell lineages, either by intrinsic defects and/or by extrinsic and maternal factors, may affect normal placenta development and function and thus contribute to the pathology of preeclampsia.
Benirschke K, Kaufmann P, Baergen R: Pathology of the human placenta. 2006, New York: Springer, 5
Vinas-Castells R, Beltran M, Valls G, Gomez I, Garcia JM, Montserrat-Sentis B, Baulida J, Bonilla F, de Herreros AG, Diaz VM: The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J Biol Chem. 2010, 285 (6): 3794-3805. 10.1074/jbc.M109.065995. PubMedCentralCrossRefPubMed
Arimoto-Ishida E, Sakata M, Sawada K, Nakayama M, Nishimoto F, Mabuchi S, Takeda T, Yamamoto T, Isobe A, Okamoto Y, et al: Up-regulation of alpha5-integrin by E-cadherin loss in hypoxia and its key role in the migration of extravillous trophoblast cells during early implantation. Endocrinology. 2009, 150 (9): 4306-4315. 10.1210/en.2008-1662. CrossRefPubMed
Fedorova OV, Simbirtsev AS, Kolodkin NI, Kotov AY, Agalakova NI, Kashkin VA, Tapilskaya NI, Bzhelyansky A, Reznik VA, Frolova EV, et al: Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension. J Hypertens. 2008, 26 (12): 2414-2425. 10.1097/HJH.0b013e328312c86a. PubMedCentralCrossRefPubMed
Fedorova LV, Raju V, El-Okdi N, Shidyak A, Kennedy DJ, Vetteth S, Giovannucci DR, Bagrov AY, Fedorova OV, Shapiro JI, et al: The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition. Am J Physiol Renal Physiol. 2009, 296 (4): F922-F934. 10.1152/ajprenal.90605.2008. PubMedCentralCrossRefPubMed
Reuss B, Hellmann P, Dahl E, Traub O, Butterweck A, Grummer R, Winterhager E: Connexins and E-cadherin are differentially expressed during trophoblast invasion and placenta differentiation in the rat. Dev Dyn. 1996, 205 (2): 172-182. 10.1002/(SICI)1097-0177(199602)205:2<172::AID-AJA8>3.0.CO;2-F. CrossRefPubMed
Vicovac L, Aplin JD: Epithelial-mesenchymal transition during trophoblast differentiation. Acta Anat (Basel). 1996, 156 (3): 202-216. 10.1159/000147847. CrossRef
Valdes F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernandez M, Benito M, Nieto MA, Fabregat I: The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res. 2002, 1 (1): 68-78. PubMed
Nieto MA, Bennett MF, Sargent MG, Wilkinson DG: Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. Development. 1992, 116 (1): 227-237. PubMed
Smith DE, Del Amo Franco F, Gridley T: Isolation of Sna, a mouse gene homologous to the Drosophila genes snail and escargot: its expression pattern suggests multiple roles during postimplantation development. Development. 1992, 116 (4): 1033-1039. PubMed
Zybina TG, Kaufmann P, Frank HG, Freed J, Kadyrov M, Biesterfeld S: Genome multiplication of extravillous trophoblast cells in human placenta in the course of differentiation and invasion into endometrium and myometrium. I. Dynamics of polyploidization. Tsitologiia. 2002, 44 (11): 1058-1067. PubMed
Zybina TG, Frank HG, Biesterfeld S, Kaufmann P: Genome multiplication of extravillous trophoblast cells in human placenta in the course of differentiation and invasion into endometrium and myometrium. II. Mechanisms of polyploidization. Tsitologiia. 2004, 46 (7): 640-648. PubMed
Schietke R, Warnecke C, Wacker I, Schodel J, Mole DR, Campean V, Amann K, Goppelt-Struebe M, Behrens J, Eckardt KU, et al: The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem. 2010, 285 (9): 6658-6669. 10.1074/jbc.M109.042424. PubMedCentralCrossRefPubMed
Burton GJ, Hung TH, Jauniaux E: Placental hypoxia, hyperoxia and ischemia-reperfusion injury in preeclampsia. Preeclampsia Etiology and Clinical Practice. Edited by: Belfort LF. 2007, Cambridge: Cambridge University Press, 138-151.
Rajakumar A, Michael HM, Daftary A, Jeyabalan A, Gilmour C, Conrad KP: Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: implications for expression of HIF-alpha proteins. Placenta. 2008, 29 (3): 290-299. 10.1016/j.placenta.2007.11.015. CrossRefPubMed
Fedorova OV, Tapilskaya NI, Bzhelyansky AM, Frolova EV, Nikitina ER, Reznik VA, Kashkin VA, Bagrov AY: Interaction of Digibind with endogenous cardiotonic steroids from preeclamptic placentae. J Hypertens. 2009, 28 (2): 361-366. CrossRef
- Down-regulation of the transcription factor snail in the placentas of patients with preeclampsia and in a rat model of preeclampsia
Joseph I Shapiro
- BioMed Central
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